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Background: Retrospective large patient database studies have reported conflicting findings regarding diabetes risks associated with antipsychotics. This study compared two study designs to assess antipsychotic-related diabetes risk., Methods: Claims data were analyzed for over 60,000 patients with psychosis, both treated and untreated with antipsychotics, between January 1999 and April 2002. Diabetes odds ratios for patients treated with antipsychotics versus untreated patients were estimated. All patients and patients stratified by low, medium, and high antipsychotic dose were analyzed. Logistic regression controlled for age, sex, type of psychosis, length of observation/treatment, preexisting excess weight, and use of other drugs., Results: Under a less rigorous study design, diabetes risk was statistically significant with all antipsychotics versus no treatment. Under a more rigorous design, relative odds for quetiapine and risperidone declined and became statistically nonsignificant, whereas those for olanzapine and conventional antipsychotics increased and remained significant. By dose, only quetiapine showed a lack of statistical significance at all dose levels., Conclusions: In database studies estimated risks of antipsychotic-related diabetes are affected by study design. With a more rigorous design, the risk associated with quetiapine and risperidone was not significantly different from that in untreated patients. These findings may explain inconsistent findings in pharmacoepidemiologic database studies.

Nephrolithiasis is a common multifactorial disorder affecting about 10% of the Western populations and it is characterized by the presence of small crystals and stones in the urinary tract. Uric acid nephrolithiasis (UAN) accounts for 20% of all stones but its prevalence varies between countries. Nephrolithiasis is likely caused by several factors but a genetic component has clearly been demonstrated. While studying an ancient founder population in Sardinia, we recently identified a susceptibility locus for UAN on chromosome 10. In this region we identified a missense mutation in a specific isoform of a novel gene is strongly associated with UAN. Through a comparative genomic approach, we did not found a mouse homolog even if we were able to identify the corresponding genomic region, while in Old World monkey we found a canonical gene structure with several stop codons preventing protein production. We detected expression in New World monkeys while in humans we observe a functional protein. It seems, therefore, that, to avoid human disease, a fierce selection worked to develop a renal-haematic urate homeostasis system against excessive hyperuricaemia. ZNF365 emerged during primate evolution and assumed its role in parallel with the disappearance of uricase, probably against a disadvantageous excessive hyperuricaemia.

Objective: To investigate the association between initial quetiapine dose and effectiveness as gauged by subsequent use of mental health services., Methods: Using a health plan database, we identified patients with bipolar disorder or schizophrenia treated with quetiapine monotherapy for at least four consecutive months. The stability of each patient before and after quetiapine treatment was measured by use of mental health services other than antipsychotic drug, measured primarily by charges reported on claims. Regression models controlling for patient differences measured associations between initial quetiapine dose and subsequent mental health service use., Results: Commercially insured patients with schizophrenia (n = 581) or bipolar disorder (n = 2421) received quetiapine monotherapy at mean (SD) initial daily doses of 237 (198) mg and 147 (171) mg, respectively. Both groups showed negative associations between initial daily dose and subsequent mental health charges. Among patients with schizophrenia, mental health charges decreased by US 1.28 dollars for each additional milligram of quetiapine (P = 0.1097). Among patients with bipolar disorder, there was a significant decrease of US 1.31 dollars per additional milligram of quetiapine (P = 0.0484). For schizophrenia, hospitalizations were reduced by 0.4% for each additional milligram of quetiapine (P = 0.0189). For bipolar disorder, the association between quetiapine dose and outpatient charges was negative and trended toward significance (P = 0.074), showing a US 0.54 dollars reduction in these charges for each additional milligram of quetiapine; the association with hospitalization was not significant., Conclusions: In patients with schizophrenia or bipolar disorder, higher initial doses of quetiapine may be more effective in stabilizing patients as reflected in lower subsequent mental health service use.

Objective: The atypical antipsychotics, risperidone, olanzapine, and quetiapine, have been approved by the U.S. Food and Drug Administration for treatment of mania associated with bipolar disorder. Information on the relative mental health resource use of these therapies is helpful to pharmacy managers since differences in efficacy and safety may translate into differences in mental health care utilization. We compared charges for other mental health services associated with risperidone, olanzapine, and quetiapine treatment of patients with bipolar disorder to assess whether there were significant differences between these therapies. A secondary analysis involved dose-equivalent adjustment of the average allowed charge of the 3 atypical antipsychotics., Methods: This was a retrospective study based on administrative data for 46 U.S. commercial health plans represented in a commercial database covering the period January 1998 through April 2002. The 6,625 patients included in the study had at least 2 contiguous pharmacy claims for a study antipsychotic, had received no other antipsychotics concurrently, and had not switched from an alternative antipsychotic in the preceding 90 days. Provider-submitted (billed) charges were selected in preference to paid amounts as being more accurate indicators of relative differences in the use of mental health resources. Mental health care charges were measured per patient per month (PPPM) and included charges for the study antipsychotics and charges for the other mental health care services (inpatient, physician and other ambulatory, and other psychotropic medications). Differences in other mental health care charges PPPM among the 3 therapies were assessed with multivariate regression, adjusting for differing patient characteristics. Differences in antipsychotic drug charges PPPM were assessed after adjustment to reflect an equivalent average daily dose., Results: Regression estimates adjusted for patient differences did not show statistically significant differences in other mental health care charges PPPM among the 3 antipsychotic drug therapies. Other mental health charges associated with quetiapine were estimated to be 14 US dollars, or 3% lower than those associated with risperidone, but this difference was not statistically significant (P = 0.069). The PPPM charges for quetiapine versus olanzapine and olanzapine versus risperidone were also not different (P = 0.231 and P = 0.39, respectively). After adjusting for differences in average daily dose, risperidone and quetiapine had antipsychotic drug charges that were 84 US dollars and 76 US dollars PPPM lower than those of olanzapine (P < 0.01); the difference between the adjusted drug charges PPPM for risperidone and quetiapine was not significant., Conclusion: Total charges for mental health services other than the study drug were not different for risperidone, olanzapine, and quetiapine in patients treated for bipolar disorder. However, based on prescription charges, olanzapine appears to be considerably more costly at an equivalent daily dose than either risperidone or quetiapine.

Recently, we identified a susceptibility locus for human uric acid nephrolithiasis (UAN) on 10q21-q22 and demonstrated that a novel gene (ZNF365) included in this region produces through alternative splicing several transcripts coding for four protein isoforms. Mutation analysis showed that one of them (Talanin) is associated with UAN. We examined the evolutionary conservation of ZNF365 gene through a comparative genomic approach. Searching for mouse homologs of ZNF365 transcripts, we identified a highly conserved mouse ortholog of ZNF365A transcript, expressed specifically in brain. We did not found a mouse homolog for ZNF365D transcript encoding the Talanin protein, even if we were able to identify the corresponding genomic region in mouse and rat not yet organized in canonical gene structure suggesting that ZNF365D was originated after the branching of hominoid from rodent lineage. In mouse and in most mammals, a functional uricase degrades the uric acid to allantoin, but uricase activity was lost during the Miocene epoch in hominoids. Searching for the presence of Talanin in Primates, we found a canonical intron-exon structure with several stop codons preventing protein production in Old World and New World monkeys. In humans, we observe expression and we have evidence that ZNF365D transcript produces a functional protein. It seems therefore that ZNF365D transcript emerged during primate evolution from a noncoding genomic sequence that evolved in a standard gene structure and assumed its role in parallel with the disappearance of uricase, probably against a disadvantageous excessive hyperuricemia.

Allelic deletions, which are suggestive for the presence of tumor suppressor genes, represent a common event in endometrial cancer (EC). Previous loss-of-heterozygosity studies for human chromosome 10q identified a candidate deletion interval at 10q25-q26, which we further narrowed to a 160-kb region at 10q26, bounded by markers D10S1236 and WIAF3299. Using a positional candidate approach, we identified three alternative transcripts of a novel human gene, CASC2 (cancer susceptibility candidate 2; formely C10orf5). One of such transcripts, CASC2a, encodes a short protein of 102 amino acids with no similarity to any other known gene product. Three (7%) CASC2a mutations were identified in tumor DNA from 44 EC patients. While c.-156G>T and c.22C>T (p.Pro8Ser) are sequence variants with unknown functional significance, c.84delA is a mutation with a truncation effect on the predicted protein (p. Asn28fsX50). Expression studies by real-time RT-PCR on several normal and tumor cells revealed that CASC2a mRNA is downregulated in cancer, suggesting that it may act as a potential tumor suppressor gene. The very low mutation rate seems to also indicate that inactivation of CASC2a might probably be due to mechanisms different from genetic alterations., (Copyright 2004 Wiley-Liss, Inc.)

Case evidence suggests that some of the atypical antipsychotics may induce type 2 diabetes. The objective of this study was to evaluate the association of antipsychotic treatment with type 2 diabetes in a large health plan database. Claims data for patients with psychosis within a health plan of nearly 2 million members were analyzed using logistic regression. Frequencies of newly treated type 2 diabetes in patients untreated with antipsychotics and among patients treated with quetiapine, risperidone, olanzapine, and conventional antipsychotics were compared. Based on exposure measured in months of antipsychotic treatment, quetiapine and risperidone patients had estimated odds of receiving treatment for type 2 diabetes that were lower than those of patients untreated with antipsychotics (not statistically significant); patients treated with conventional antipsychotics had estimated odds that were virtually equivalent to those of patients untreated with antipsychotics; olanzapine alone had odds that were significantly greater than those of patients untreated with antipsychotics (P = 0.0247). Odds ratios based on 8 months of screening for pre-existing type 2 diabetes and assuming 12 months of antipsychotic treatment were: risperidone = 0.660 (95% CI 0.311-1.408); olanzapine = 1.426 (95% CI 1.046-1.955); quetiapine = 0.976 (95% CI 0.422-2.271); and conventional antipsychotics = 1.049 (95% CI 0.688-1.613). Case reports, prospective trials, and other retrospective studies have increasingly implicated olanzapine and clozapine as causing or exacerbating type 2 diabetes. Few have implicated risperidone while evidence on quetiapine has been limited. This study supports earlier findings on risperidone versus olanzapine and builds evidence on quetiapine. Additional studies are needed to evaluate the association of antipsychotic treatment with type 2 diabetes.

Uric acid nephrolithiasis (UAN) is a common disease with an established genetic component that presents a complex mode of inheritance. While studying an ancient founder population in Talana, a village in Sardinia, we recently identified a susceptibility locus of approximately 2.5 cM for UAN on 10q21-q22 in a relatively small sample that was carefully selected through genealogical information. To refine the critical region and to identify the susceptibility gene, we extended our analysis to severely affected subjects from the same village. We confirm the involvement of this region in UAN through identical-by-descent sharing and autozygosity mapping, and we refine the critical region to an interval of approximately 67 kb associated with UAN by linkage-disequilibrium mapping. After inspecting the genomic sequences available in public databases, we determined that a novel gene overlaps this interval. This gene is divided into 15 exons, spanning a region of approximately 300 kb and generating at least four different proteins (407, 333, 462, and 216 amino acids). Interestingly, the last isoform was completely included in the 67-kb associated interval. Computer-assisted analysis of this isoform revealed at least one membrane-spanning domain and several N- and O-glycosylation consensus sites at N-termini, suggesting that it could be an integral membrane protein. Mutational analysis shows that a coding nucleotide variant (Ala62Thr), causing a missense in exon 12, is in strong association with UAN (P=.0051). Moreover, Ala62Thr modifies predicted protein secondary structure, suggesting that it may have a role in UAN etiology. The present study underscores the value of our small, genealogically well-characterized, isolated population as a model for the identification of susceptibility genes underlying complex diseases. Indeed, using a relatively small sample of affected and unaffected subjects, we identified a candidate gene for multifactorial UAN.

Background: Atypical antipsychotics are being used increasingly in the management of mood disorders., Objective: The objective of this study was to investigate the association between exposure to antipsychotic therapy and newly reported type 2 diabetes mellitus in patients with mood disorders., Methods: Claims data for the period January 1996 through December 1997 were analyzed for patients with mood disorders in 2 large US health plans. Logistic regression models were used to determine the odds of reporting diabetes in patients exposed to risperidone, olanzapine, or high- or low-potency conventional antipsychotics compared with untreated patients, taking into account duration of treatment and dosage. Some of the covariates used in the models were concurrent use of antipsychotics, use of other psychotropic drugs, age, sex, and length of observation., Results: Based on the claims data, 849 patients were exposed to risperidone, 656 to olanzapine, 785 to high-potency conventional antipsychotics, and 302 to low-potency conventional antipsychotics; 2644 patients were untreated. The odds of newly reported type 2 diabetes in patients who received risperidone were not significantly different from those in untreated patients (12-month odds ratio [OR] = 1.024; 95% CI, 0.351-3.015). The odds in patients treated with high-potency conventional antipsychotics also did not differ significantly from those of untreated patients (12-month OR = 1.945; 95% CI, 0.794-4.786). Unlike patients who received risperidone or high-potency conventional antipsychotics, patients who received olanzapine (12-month OR = 4.289; 95% CI, 2.102-8.827) and low-potency conventional antipsychotics (12-month OR = 4.972; 95% CI, 1.967-12.612) had significantly higher odds for the development of type 2 diabetes compared with untreated patients., Conclusions: These findings suggest that some antipsychotics may increase the risk for the development of type 2 diabetes in patients with mood disorders and that the effect may vary by drug. In contrast to olanzapine and low-potency conventional antipsychotics, risperidone and high-potency conventional antipsychotics were not associated with an increased risk for development of type 2 diabetes in this patient population.

Members of phosphoinositide-specific phospholipase C (PLC) families are central intermediary in signal transduction in response to the occupancy of receptors by many growth factors. Among PLC isoforms, the type beta(1) is of particular interest because of its reported nuclear localisation in addition to its presence at the plasma membrane. It has been previously shown that both the stimulation and the inhibition of the nuclear PLCbeta(1) under different stimuli implicate PLCbeta(1) as an important enzyme for mitogen-activated cell growth as well as for murine erythroleukaemia cell differentiation. The above findings hinting at a direct involvement of PLCbeta(1) in controlling the cell cycle in rodent cells, and the previously reported mapping of its gene in rat chromosome band 3q35-36, a region frequently rearranged in rat tumours induced by chemical carcinogenesis, prompted us to identify its human homologue. By screening a human foetal brain cDNA library with the rat PLCbeta(1) cDNA probe, we have identified a clone homologous to a sequence in gene bank called KIAA 0581, which encodes a large part of the human PLCbeta(1). By using this human cDNA in fluorescence in situ hybridisation on human metaphases, it has been possible to map human PLCbeta(1) on chromosome 20p12, confirming the synteny between rat chromosome 3 and human chromosome 20 and providing a novel locus of homology between bands q35-36 in rat and p12 in man. Since band 20p12 has been recently reported amplified and/or deleted in several solid tumours, the identification and chromosome mapping of human PLCbeta(1) could pave the way for further investigations on the role exerted both in normal human cells and in human tumours by PLCbeta(1), which has been shown to behave as a key signalling intermediate in the control of the cell cycle.

Human sex chromosomes, which are morphologically and genetically different, share few regions of homology. Among them, only pseudoautosomal regions (PARs) pair and recombine during meiosis. To better address the complex biology of these regions, we sequenced the telomeric 400 kb of the long arm of the human X chromosome, including 330 kb of the human Xq/YqPAR and the telomere. Sequencing reveals subregions with distinctive regulatory and evolutionary features. The proximal 295 kb contains two genes inactivated on both the inactive X and Y chromosomes [ SYBL1 and a novel homologue ( HSPRY3 ) of Drosophila sprouty ]. The GC-rich distal 35 kb, added in stages and much later in evolution, contains the X/Y expressed gene IL9R and a novel gene, CXYorf1, only 5 kb from the Xq telomere. These properties make Xq/YqPAR a model for studies of region-specific gene inactivation, telomere evolution, and involvement in sex-limited conditions.

We report the cloning of a novel gene, called Tramp, in the Xp/Yp PAR region that has a functional homologue on the Y chromosome and escapes X-inactivation. This gene encodes, within a single exon, a putative protein that has amino acid similarity with transposases of the Ac family. Flanking this gene we have identified putative terminal inverted repeats (TIRs) and a duplicate target site, suggesting that it may be an ancient transposable element. The nucleotide differences in these sites and the TIR-binding inactivity of the putative Tramp protein suggest that this element is not an autonomous transposon. In the human genome, the Tramp protein may be involved in the transposition of other transposable elements, like medium reiterated frequency repeats, or it could be specialized in the acquisition of a new cellular function.

Most genes on the X chromosome undergo "inactivation," being transcribed from only one copy in female somatic cells, but several human genes have been shown to be expressed from both the active and the otherwise inactivated homologue. To assess further the fraction and location of genes that escape inactivation, we have analyzed the inactivation status of a set of 73 expressed sequence tags that were derived from the sequencing of cDNA collections and mapped to the X chromosome. Of 33 that were expressed in cultured cells, as assessed by reverse transcription and PCR, 4 (about 12%) were transcribed from both the active and the inactive X chromosome. Two, RPS4 and PCTAIRE1, are already known to escape inactivation; the other 2, of unknown function, include a short cDNA with a full open reading frame and a transcript with no detectable open reading frame. They map, respectively, to Xp11.3-p11.4 and Xp22.2; both regions were previously reported to encode sequences transcribed from the inactive X. Neither transcript has a corresponding sequence on the Y. Thus, they exhibit double dosage in females compared to males, and inactivation status may be inconsequential for these transcribed sequences.

The X and Y chromosomes that maintain human dimorphism are thought to have descended from a single progenitor, with the Y chromosome becoming largely depleted of genes. A number of genes, however, retain copies on both X and Y chromosomes and escape the inactivation that affects most X-linked genes in somatic cells. Many of those genes are present in two pseudoautosomal regions (PARs) at the termini of the short (p) and long (q) arms of the sex chromosomes. For both PARs, pairing facilitates the exchange of information, ensuring the homogenisation of X and Y chromosomal material in these regions. We report here a strikingly different regulation of expression of a gene in Xq PAR. Unlike all Xp PAR genes studied so far, a synaptobrevin-like gene, tentatively named SYBL1, undergoes X inactivation. In addition, it is also inactive on the Y chromosome, thereby maintaining dosage compensation in an unprecedented way.

In this article, the effects of prescription drug coverage on use are analyzed for beneficiaries of a large retiree health benefit fund in a quasi-experiment comparing new and established enrollees. Newer enrollees show an 18-percentage point greater increase in prescription drug expenditures per capita than established enrollees during the 3-year period following enrollment. This differential is interpreted as the insurance effect of prescription coverage. The impact was greater among high-cost drugs than among low-cost drugs, and also greater among low users of prescription drugs than among high users. No clear patterns were discerned across therapeutic categories.

We analyzed alternative payment approaches that Medicare could use to pay for recombinant human erythropoietin (rHuEPO) therapy. How Medicare pays for rHuEPO therapy will affect whether providers make prudent purchases of the biologic and prescribe it appropriately and whether companies offer the program low prices. Medicare's policies may also guide policies of other third parties. Selecting payment options for Medicare payment requires balancing desirable and undesirable implications, especially trade-offs between improving access to and quality of care for beneficiaries versus constraining costs to Medicare and its beneficiaries. The options for paying providers that contain financial incentives to constrain expenditures also contain incentives for providers to skimp on use, perhaps to the detriment of patients' quality of care. On the other hand, options that may reward additional use may lead to higher expenditures and threaten the quality of care from the direction of overuse. Medicare currently varies the level and method of payment for rHuEPO therapy according to the setting in which it is provided. Equity among beneficiaries and providers and incentives for efficient use of medical services would argue for paying the same amount for the same service, regardless of where it was provided. Whatever payment options are adopted, the Health Care Financing Administration (HCFA) will have to be able to exercise flexibility in monitoring and responding to changing market conditions. In this dynamic market, the number of manufacturers, medical indications for use approved by the Food and Drug Administration, and, eventually, Medicare's predominance are likely to evolve over time. The appropriate level and perhaps even the method of payment may well change with market conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

The biologic recombinant human erythropoietin provides a recent case study of the great influence federal policies, especially Medicare payment, exert over the use and cost of medical technologies. By covering most dialysis patients, Medicare has been the predominant payer for recombinant erythropoietin, which corrects anemia associated with chronic renal disease. Medicare's leverage seems to have produced a low US price for the product. Paying a fixed rate per treatment with the biologic agent gave dialysis facilities a financial incentive to use low doses, but Medicare did not routinely monitor patients' responses. By August 1990, average and modal doses were low, and fewer than 45% of patients who had been treated for 6 months or more had ever attained the target hematocrit. Medicare should recognize the financial incentives of its payment policies and routinely evaluate the quality of care for beneficiaries.

The effects of the prospective payment system and other factors on the use of post-hospital services were investigated for four groups of diagnostically related Medicare discharges. Effects on specific services and total Medicare payments were analyzed at the beneficiary level using a Tobit regression technique. The utilization data base consisted of more than 30,000 discharge episode records for the years 1981-86. The post-hospital period for each Medicare beneficiary encompassed the 60 days following discharge from the hospital. Influences on both the level and timing of health care services during this period were appraised. The influence of the prospective payment system was measured through the financial impact and risk that it imposed on the discharging hospital.

In FY 1984 the Medicare program implemented a new method of reimbursing hospitals for inpatient services, the Prospective Payment System (PPS). Under this system, hospitals are paid a predetermined amount per Medicare discharge, which varies according to certain patient and hospital characteristics. This article investigates the presence of systematic biases and other potential imperfections in the PPS reimbursement methodology as revealed by its effects on Medicare operating ratios. The study covers the first three years of the PPS (approximately 1984-1986) and is based on hospital data from the Medicare cost reports and other related sources. Regression techniques were applied to these data to determine how Medicare operating ratios were affected by specific aspects of the reimbursement methodology. Several possible imbalances were detected. The potential undercompensation relating to these can be harmful to certain classes of hospitals and to the Medicare populations that they serve.